Abstract
Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people. To improve the drug delivery profile, we created a myristoylated CAB prodrug (MCAB). MCAB formed crystals that were formulated into nanoparticles (NMCAB) of stable size and shape facilitating avid monocyte-macrophage entry, retention and reticuloendothelial system depot formulation. Drug release kinetics paralleled sustained protection against HIV-1 challenge. After a single 45 mg/kg intramuscular injection to BALB/cJ mice, the NMCAB pharmacokinetic profiles was 4-times greater than that recorded for CAB LAP. These observations paralleled replicate measurements in rhesus macaques. The results coupled with improved viral restriction in human adult lymphocyte reconstituted NOD/SCID/IL2Rγc−/− mice led us to conclude that NMCAB can improve biodistribution and viral clearance profiles upon current CAB LAP formulations.
Highlights
Following the 1983 discovery of the human immunodeficiency virus type one (HIV-1), remarkable progress was made in the development of effective diagnostics and treatments [1]
Monoclonal mouse anti-human HIV-1p24, monoclonal mouse anti-human leukocyte antigen (HLA-DR; clone CR3/43), and the polymer-based HRP-conjugated anti-mouse EnVision + secondary were purchased from Dako (Carpinteria, CA, USA)
The chemical structure of myristoylated CAB prodrug (MCAB) was characterized by 1H NMR and FTIR spectra and compared to CAB as shown in Fig. S1 and Fig. 1B
Summary
Following the 1983 discovery of the human immunodeficiency virus type one (HIV-1), remarkable progress was made in the development of effective diagnostics and treatments [1]. The most successful of all is effective antiretroviral therapy (ART). ART has markedly reduced disease-associated morbidities and mortality, enabling a nearly normal quality of life for infected people [2,3]. Life-long treatment is still required to suppress viral replication and contain disease. HIV-1 resistance [4,5], drug toxicities [6,7], and poor patient adherence [8] have impeded therapeutic effectiveness. Lack of financial and social support, co-existing mental symptoms, and substance abuse can result in lack of adherence to ART regimens [9].
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